Jump to

Since the demonstration that ST-segment depression is commonly found on the ECGs of coronary artery disease (CAD) patients during stress, graded exercise testing with ECG monitoring has been used to identify patients likely (and unlikely) to have CAD with flow-limiting stenoses that cause myocardial ischemia. Unfortunately, the clinical value of the exercise ECG as a diagnostic test for CAD has been limited by the imperfect association between ST-segment depression (even if >1.0 mm with horizontal or downsloping configuration) and angiographically significant coronary artery lesions, and by use of testing in populations at various degrees of risk for disease.123

Investigators have derived variations of ECG analysis in an attempt to improve the sensitivity of exercise testing for diagnosing CAD, such as heart rate adjustments of ST-segment depression (ST/heart rate slope, ST/heart rate index) during exercise.45 However, these analyses are not widely used, in part because of continued dispute regarding the advantages of these data manipulations over conventional ST-segment analysis alone.67 Frustrated by limitations in the diagnostic utility of the exercise ECG, many cardiologists initially perform nuclear or echocardiographic stress (exercise or pharmacological) testing to diagnose CAD in patients with unknown coronary anatomy or go straight to coronary angiography without prior noninvasive stress testing.8

In this issue of Circulation, Barthélémy and coworkers9 report a novel approach to analyzing the response to exercise stress, which they believe enhances the clinical usefulness of exercise testing in diagnosing CAD. In addition to recording the ECG and vital signs during exercise, the authors measured plasma lactate levels within minutes after termination of exercise. Lactic acid is released by exercising skeletal muscles as the oxygen requirements of working muscle cells exceed adequate oxygen delivery to the cells (the so-called oxygen debt).

Appropriate oxygen delivery is determined by the oxygen-carrying capacity of blood and adequate skeletal muscle perfusion, which in turn is determined by the cardiac output response to exercise and the magnitude of vasodilation in working skeletal muscles. At low workloads, plasma lactate levels are low because of adequate or near-adequate muscle oxygenation. However, as the intensity of exercise increases and muscles work harder, lactate release increases substantially and blood lactate levels rise, with potential development of a metabolic acidosis if the buffering capacity of bicarbonate in the blood is exceeded. This point of rapid increase in plasma lactate levels during strenuous exercise has been called the “anaerobic threshold,” indicative of a shift from aerobic to anaerobic metabolism in working muscles.10 Beyond this threshold, continued exercise results in rapid increases in plasma lactate levels until exercise is terminated. Wasserman and coworkers10 have estimated that the anaerobic threshold in normal individuals is measurable at ≈55% of their maximum exercise capacity. However, there is variability in the onset of this threshold because of the level of fitness and training (which affects both the cardiac output response to exercise and skeletal muscle perfusion during exercise) and the oxygen-carrying capacity of blood.

The patient cohort of Barthélémy and coworkers9 consisted of 236 symptomatic men with normal ECGs at rest referred for suspicion of CAD. Although an assessment of resting left ventricular function was not reported, patients had no evidence of prior myocardial infarction, cardiomyopathy, or valvular heart disease. Exercise was performed using a bicycle ergometer, with the beginning load and load increases during exercise individualized such that the total exercise would last approximately 10 minutes. The exercise test was discontinued with notation of horizontal ST-segment depression ≥1.0 mm (or upsloping ST-segment depression ≥1.5 mm), angina pectoris, or exhaustion. All patients in this series underwent catheterization, including 146 with ST-segment criteria for a “positive” test; the remaining 90 patients with a “negative” ECG response underwent catheterization because of specific referral instructions at the participating institutions. The authors reported that the plasma lactate levels of the 153 patients with CAD (≥70% luminal diameter narrowing of at least one major coronary artery) were significantly lower than those of the 83 patients without CAD (7.68±0.42 versus 10.56±0.51 mmol/L, P<.0001).

Construction of receiver operator curves, which describe the relationship between sensitivity and specificity of a test result in determining the presence or absence of disease, showed highly significant areas under these curves (W values) for plasma lactate levels as well as conventional exercise test parameters: maximum load, exercise duration, percent maximum predicted heart rate, maximum ST-segment depression, age, and heart rate–systolic blood pressure product (in descending order of W values). By multiple logistic regression analysis, only the plasma lactate level and presence of angina during the test appeared to be independently and significantly associated with the presence of angiographically significant CAD. On the basis of plasma lactate levels, the authors then constructed a decision tree, with input of exercise hemodynamic and ST-segment response variables along with plasma lactate levels between the highest and lowest values. By use of this decision tree in their study population, the authors reported a negative predictive value of 96% and a positive predictive value of 97% for their testing in the determination of angiographically significant stenoses involving at least one major coronary artery.

The use of plasma lactate levels as a determinant of CAD has intuitive appeal, because patients with myocardial ischemia during exercise stress would likely not exercise as far or to as high a workload as healthy subjects, either because of angina pectoris and/or dyspnea due to myocardial ischemia or, as in this study, because the physician stops the test upon ECG evidence of ischemia. However, the success of plasma lactate levels as an important discriminant in detecting CAD in this study required considerable cardiologist input, not only in stopping the test at the earliest ECG evidence of ischemia but also in determining the ergometer loads at which to initiate exercise and the load increments for escalation during bicycle exercise. Very likely, the cardiologist chose lower initiating workloads and lower workload increments during exercise for patients who provided a history of angina-like pain or effort dyspnea likely to be a consequence of myocardial ischemia and chose higher workloads for individuals without any history of effort intolerance or individuals with atypical chest pain syndromes. Because the magnitude of lactate release depends in large part on the exercise load and thus skeletal muscle work, one might have been able to roughly predict the ultimate lactate levels on the basis of the clinical determinants that led the cardiologist to choose a particular exercise regimen, with further refinement in this prediction by observing ischemic-appearing ST-segment changes or angina during the test. Thus, in a population at risk for CAD referred for cardiac evaluation (such as the middle-aged and older men participating in this study), the clinical history may be as good a discriminant for the presence or absence of hemodynamically significant CAD as the exercise ECG and, very likely, as the plasma lactate level obtained soon after exercise. Indeed, in this study, angina during exercise testing was a more powerful predictor of angiographically significant CAD than the plasma lactate level, indicative of the high pretest likelihood of disease in their symptomatic study population.

Further, plasma lactate levels as determinants of CAD may not be useful in standardized exercise testing in which relatively large increments in workload changes are used during the course of the exercise test (such as the standard Bruce protocol), when patients develop left ventricular dysfunction during exercise, or when exercise testing is allowed to continue beyond 1.0-mm horizontal ST depression in an attempt to obtain prognostic information. Indeed, it is this last point that diminishes the usefulness of plasma lactate levels during exercise testing: The magnitude of plasma lactate level elevation bore no relation to the angiographic extent of CAD in the authors’ study. Treadmill exercise testing, as is true for nuclear and echocardiographic stress testing, is used not only to diagnose CAD but also more commonly to obtain information regarding the likely extent and severity of CAD, findings with important prognostic implications. Further, in a population of patients at low risk for CAD, termination of exercise at an early stage because of a “false-positive” ST-segment response might be associated with a relatively low plasma lactate level, thus diminishing the specificity of plasma lactate level as a determinant of angiographically significant disease.

Although conventional exercise testing with analysis of ST-segment changes may be less commonly used by cardiologists for the purpose of diagnosing CAD, it is being more commonly used by internists and other “gatekeepers” to determine the need for cardiology referral.11 Cardiologists and noncardiologists alike need to know which variables permit optimal (≈70%) sensitivity and specificity in the performance of exercise testing for the purpose of diagnosing CAD; attention to skin preparation and electrode placement for 12-lead ECG recording, exclusion of patients with abnormal rest ECGs (including left ventricular hypertrophy), performance of study off medications (especially digoxin), avoidance of preexercise hyperventilation, adequate exercise performance, and acceptance of horizontal or downsloping ST-segment depression >1.0 mm during or after exercise or ST-segment elevation in the absence of baseline pathological Q waves as evidence for ischemia.12 In a patient population at intermediate to high risk for CAD, the positive and negative predictive values of exercise test results with attention to these considerations should be sufficient to justify continued use of this relatively inexpensive test modality, recognizing that test results provide only estimates of the probability of significant CAD. Equivocal or nondiagnostic studies should be repeated with nuclear or echocardiographic imaging during exercise or pharmacological stress. The necessity of adding plasma lactate measurement should await proof of its independent diagnostic value in large, unselected patient populations undergoing diagnostic testing for CAD.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.